A Functionally Conserved Gene Regulatory Network Module Governing Olfactory Neuron Diversity.

Sensory neuron diversity is required for organisms to decipher complex environmental cues. In Drosophila, the olfactory environment is detected by 50 different olfactory receptor neuron (ORN) classes that are clustered in combinations within distinct sensilla subtypes. Each sensilla subtype houses stereotypically clustered 1-4 ORN identities that arise through asymmetric divisions from a single multipotent sensory organ precursor (SOP). How each class of SOPs acquires a unique differentiation potential that accounts for ORN diversity is unknown. Previously, we reported a critical component of SOP diversification program, Rotund (Rn), increases ORN diversity by generating novel developmental trajectories from existing precursors within each independent sensilla type lineages. Here, we show that Rn, along with BarH1/H2 (Bar), Bric-à-brac (Bab), Apterous (Ap) and Dachshund (Dac), constitutes a transcription factor (TF) network that patterns the developing olfactory tissue. This network was previously shown to pattern the segmentation of the leg, which suggests that this network is functionally conserved. In antennal imaginal discs, precursors with diverse ORN differentiation potentials are selected from concentric rings defined by unique combinations of these TFs along the proximodistal axis of the developing antennal disc. The combinatorial code that demarcates each precursor field is set up by cross-regulatory interactions among different factors within the network. Modifications of this network lead to predictable changes in the diversity of sensilla subtypes and ORN pools. In light of our data, we propose a molecular map that defines each unique SOP fate. Our results highlight the importance of the early prepatterning gene regulatory network as a modulator of SOP and terminally differentiated ORN diversity. Finally, our model illustrates how conserved developmental strategies are used to generate neuronal diversity.

Myocardial Contractile Mechanics in Ischemic Mitral Regurgitation: Multicenter Data Using Stress Perfusion Cardiovascular Magnetic Resonance.

BACKGROUND: Left ventricular (LV) ischemia has been variably associated with functional mitral regurgitation (FMR). Determinants of FMR in patients with ischemia are poorly understood. OBJECTIVES: This study sought to test whether contractile mechanics in ischemic myocardium underlying the mitral valve have an impact on likelihood of FMR. METHODS: Vasodilator stress perfusion cardiac magnetic resonance was performed in patients with coronary artery disease (CAD) at multiple centers. FMR severity was confirmed quantitatively via core lab analysis. To test relationship of contractile mechanics with ischemic FMR, regional wall motion and strain were assessed in patients with inducible ischemia and minimal (≤5% LV myocardium, nontransmural) infarction. RESULTS: A total of 2,647 patients with CAD were studied; 34% had FMR (7% moderate or greater). FMR severity increased with presence (P < 0.001) and extent (P = 0.01) of subpapillary ischemia: patients with moderate or greater FMR had more subpapillary ischemia (odds ratio [OR]: 1.13 per 10% LV; 95% CI: 1.05-1.21; P = 0.001) independent of ischemia in remote regions (P = NS); moderate or greater FMR prevalence increased stepwise with extent of ischemia and infarction in subpapillary myocardium (P < 0.001); stronger associations between FMR and infarction paralleled greater wall motion scores in infarct-affected territories. Among patients with inducible ischemia and minimal infarction (n = 532), wall motion and radial strain analysis showed impaired subpapillary contractile mechanics to associate with moderate or greater FMR (P < 0.05) independent of remote regions (P = NS). Conversely, subpapillary ischemia without contractile dysfunction did not augment FMR likelihood. Mitral and interpapillary dimensions increased with subpapillary radial strain impairment; each remodeling parameter associated with impaired subpapillary strain (P < 0.05) independent of remote strain (P = NS). Subpapillary radial strain (OR: 1.13 per 5% [95% CI: 1.02-1.25]; P = 0.02) and mitral tenting area (OR: 1.05 per 10 mm2 [95% CI: 1.00-1.10]; P = 0.04) were associated with moderate or greater FMR controlling for global remodeling represented by LV end-systolic volume (P = NS): when substituting sphericity for LV volume, moderate or greater FMR remained independently associated with subpapillary radial strain impairment (OR: 1.22 per 5% [95% CI: 1.02-1.47]; P = 0.03). CONCLUSIONS: Among patients with CAD and ischemia, FMR severity and adverse mitral apparatus remodeling increase in proportion to contractile dysfunction underlying the mitral valve.

Cerebral white matter connectivity, cognition, and age-related macular degeneration.

Age-related macular degeneration (AMD) is a common retina disease associated with cognitive impairment in older adults. The mechanism(s) that account for the link between AMD and cognitive decline remain unclear. Here we aim to shed light on this issue by investigating whether relationships between cognition and white matter in the brain differ by AMD status. In a direct group comparison of brain connectometry maps from diffusion weighted images, AMD patients showed significantly weaker quantitative anisotropy (QA) than healthy controls, predominantly in the splenium and left optic radiation. The QA of these tracts, however, did not correlate with the visual acuity measure, indicating that this group effect is not directly driven by visual loss. The AMD and control groups did not differ significantly in cognitive performance.Across all participants, better cognitive performance (e.g. verbal fluency) is associated with stronger connectivity strength in white matter tracts including the splenium and the left inferior fronto-occipital fasciculus/inferior longitudinal fasciculus. However, there were significant interactions between group and cognitive performance (verbal fluency, memory), suggesting that the relation between QA and cognitive performance was weaker in AMD patients than in controls.This may be explained by unmeasured determinants of performance that are more common or impactful in AMD or by a recruitment bias whereby the AMD group had higher cognitive reserve. In general, our findings suggest that neural degeneration in the brain might occur in parallel to AMD in the eyes, although the participants studied here do not (yet) exhibit overt cognitive declines per standard assessments.

Relating Sensory, Cognitive, and Neural Factors to Older Persons' Perceptions about Happiness: An Exploratory Study.

Despite increased rates of disease, disability, and social losses with aging, seniors consistently report higher levels of subjective well-being (SWB), a construct closely related to happiness, than younger adults. In this exploratory study, we utilized an available dataset to investigate how aspects of health commonly deteriorating with age, including sensory (i.e., vision and hearing) and cognitive status, relate to variability in self-described contributors to happiness. Community-dwelling seniors (n = 114) responded to a single-item prompt: "name things that make people happy." 1731 responses were categorized into 13 domains of SWB via structured content analysis. Sensory health and cognition were assessed by Snellen visual acuity, pure-tone audiometry, and in-person administration of the Brief Test of Adult Cognition by Telephone (BTACT) battery. A subset of eligible participants (n = 57) underwent functional magnetic resonance imaging (fMRI) to assess resting state functional connectivity (FC) within a previously described dopaminergic network associated with reward processing. SWB response patterns were relatively stable across gender, sensory status, and cognitive performance with few exceptions. For example, hearing-impaired participants listed fewer determinants of SWB (13.59 vs. 17.16; p < 0.001) and were less likely to name things in the "special events" category. Participants with a higher proportion of responses in the "accomplishments" domain (e.g., winning, getting good grades) demonstrated increased FC between the ventral tegmental area and nucleus accumbens, regions implicated in reward and motivated behavior. While the framework for determinants of happiness among seniors was largely stable across the factors assessed here, our findings suggest that subtle changes in this construct may be linked to sensory loss. The possibility that perceptions about determinants of happiness might relate to differences in intrinsic connectivity within reward-related brain networks also warrants further investigation.